Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases. Issue 3 (20th December 2018)

• Record Type: Journal Article
• Authors: Acosta-Herrera, Marialbert; Kerick, Martin; González-Serna, David; Wijmenga, Cisca; Franke, Andre; Gregersen, Peter K; Padyukov, Leonid; Worthington, Jane; Vyse, Timothy James; Alarcón-Riquelme, Marta Eugenia; Mayes, Maureen D; Martin, Javier
• Other Names: author non-byline.; Miller Frederick W author non-byline.; Chen Wei author non-byline.; O'Hanlon Terrance P author non-byline.; Cooper Robert G author non-byline.; Vencovsky Jiri author non-byline.; Rider Lisa G author non-byline.; Danko Katalin author non-byline.; Wedderburn Lucy R author non-byline.; Lundberg Ingrid E author non-byline.; Pachman Lauren M author non-byline.; Reed Ann M author non-byline.; Ytterberg Steven R author non-byline.; Callaghan Albert Selva-O' author non-byline.; Radstake Timothy R author non-byline.; Isenberg David A author non-byline.; Chinoy Hector author non-byline.; Ollier William E R author non-byline.; Scheet Paul author non-byline.; Peng Bo author non-byline.; Lee Annette author non-byline.; Lamb Janine A author non-byline.; Amos Christopher I author non-byline.; Denton Christopher author non-byline.; Hilton-Jones David author non-byline.; Plotz Paul H author non-byline.; Varsani Hemlatha author non-byline.; author non-byline.; Radstake Timothy R D J author non-byline.; Gorlova Olga author non-byline.; Rueda Blanca author non-byline.; Martin Jose-Ezequiel author non-byline.; Alizadeh Behrooz Z author non-byline.; Palomino-Morales Rogelio author non-byline.; Coenen Marieke J author non-byline.; Vonk Madelon C author non-byline.; Voskuyl Alexandre E author non-byline.; Scheurwegh Annemie J author non-byline.; Broen Jasper C author non-byline.; van Riel Piet L C M author non-byline.; van 't Slot Ruben author non-byline.; Italiaander Annet author non-byline.; Ophoff Roel A author non-byline.; Riemekasten Gabriela author non-byline.; Hunzelmann Nico author non-byline.; Simeon Carmen P author non-byline.; Ortego-Centeno Norberto author non-byline.; González-Gay Miguel A author non-byline.; González-Escribano María F author non-byline.; Airo Paolo author non-byline.; van Laar Jaap author non-byline.; Herrick Ariane author non-byline.; Hesselstrand Roger author non-byline.; Smith Vanessa author non-byline.; de Keyser Filip author non-byline.; Houssiau Fredric author non-byline.; Chee Meng May author non-byline.; Madhok Rajan author non-byline.; Shiels Paul author non-byline.; Westhovens Rene author non-byline.; Kreuter Alexander author non-byline.; Kiener Hans author non-byline.; de Baere Elfride author non-byline.; Witte Torsten author non-byline.; Klareskog Lars author non-byline.; Beretta Lorenzo author non-byline.; Scorza Rafaella author non-byline.; Lie Benedicte A author non-byline.; Hoffman-Vold Anna-Maria author non-byline.; Carreira Patricia author non-byline.; Varga John author non-byline.; Hinchcliff Monique author non-byline.; Lee Annette T author non-byline.; Ying Jun author non-byline.; Han Younghun author non-byline.; Weng Shih-Feng author non-byline.; Wigley Fredrick M author non-byline.; Hummers Laura author non-byline.; Nelson J Lee author non-byline.; Agarwal Sandeep K. author non-byline.; Assassi Shervin author non-byline.; Gourh Pravitt author non-byline.; Tan Filemon K author non-byline.; Koeleman Bobby P C author non-byline.; Arnett Frank C author non-byline.;
• Is Part Of: Annals of the rheumatic diseases. Volume 78:Issue 3(2019)
• Page Start: 311
• Page End: 319
• Publication Date: 2018-12-20
• Subjects: gene polymorphism -- autoimmune diseases -- autoimmunity; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-214127
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objective: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12 . All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci . Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.